PROJECT SUMMARY Major second Depressive Disorder (MDD) is the most prevalent mental illness, and has been estimated to be the leading cause of disability worldwide. However, standard treatments for MDD typically take at least 2-3 weeks to take effect, prolonging disease burden. In order to create novel, fast-acting therapies, a better understanding of the underlying mechanisms responsible for the development and maintenance of MDD is needed. It ketamine MDD. is hypothesized that the common factor among current rapid antidepressant interventions, including and sleep deprivation, is a change i n synaptic plasticity, which has been suggested to be impaired in Slow-wave activity (SWA) during sleep has been implicated in modulating synaptic plasticity; however the link between SWA, plasticity, and depression has yet to be determined. The proposed research aims to examine the role of sleep SWA in modulating mood by testing the model that disrupting SWA during sleep can prevent homeostatic decreases in plasticity, thereby increasing plasticity and improving mood in individuals with MDD. In this Mentored Patient-Oriented Research Career Development Award (K23) application, the candidate will pursue these research aims in the context of interdisciplinary training that builds on her expertise in the role of sleep homeostasis in depression and sleep research methodology with (1) neuroscience stimulation, including clinical training in the of synaptic plasticity and multi-modal assessment methods (e.g., transcranial magnetic analysis of waking EEG, measurement of BDNF), (2) advanced training in quantitative EEG analytic approaches, and (3) advanced training in MDD research (e.g., neurobiology of MDD, and trials methodology).These training goals will support the candidate's long term goal of becoming an independent translational scientist in patient-oriented research, and are central to the execution of the proposed research plan. Forty history males and females with MDD (25-50 yo), and a group of twenty controls with no of mood disorders will spend two nights in the laboratory: one baseline night of sleep, and one night where slow-wave sleep will be disrupted utilizing a validated procedure. Following markers indirect serum will wave each laboratory night, associated with net synaptic strength and plasticity will be assessed using several independent, but indices including waking EEG theta power metrics derived from t ranscranial magnetic stimulation, derived BDNF, and behavioral measures of learning and memory. It is predicted that those with MDD exhibit markers associated with deficient net synaptic strength and plasticity at baseline, and that slow- disruption will normalize these measures, thereby improving mood , . This project has the potential to identify the mechanisms by which sleep affects mood in MDD, which could inform the development of novel interventions.